The pathogenetic process by which progressive inflammatory injury to the lung develops, is poorly understood. Multiple causative agents may initiate the process and many mediation pathways are involved in the subsequent tissue damage and loss of pulmonary function. Our objective is to delineate the mechanisms which lead to chronic lung injury. Our approach is to first define in detail the mechanisms by which acute inflammatory reactions in the lung produce its injury. We will induce a variety of individual and then superimposed injurious reactions in rabbits and rats, both by the airways and the circulation. These will comprise immunologic and non-immunologic inciting agents including the initiation of reactions with IgA and IgE immunoglobulin in the airways, IgE and IgG systematically and the effects of inorganic particles (kaolin), lipopolysaccharide, and altered blood gas tension. We will assess the injurious process by determination of changes in pulmonary function; histology; vascular permeability; mediator-cell accumulation; activation and secretion; and the deposition and activation of components of plasma-protein in mediation systems. Concurrent analysis of the mediation processes in vitro will subsequently allow manipulation of the experimental, in vivo, injury to pinpoint particular pathogenetic mechanisms. We will determine specifically, by which, of a number of potential inciting stimuli, an inflammatory cell has been activated in vivo, by identification of specific cell desensitization to a given stimulus. This will allow us, for example, to determine whether mast cells have degranulated as a response to an IgE reaction or to the products (anaphylatoxin) of complement activation. Finally we will induce and study repeated acute reactions in the lungs, in the belief that as we have demonstrated in glomerulonephritis, multiple, acute injurious insults to the lung will lead to chronic inflammatory injury. The experiments will demonstrate the pathogenetic mechanisms of development of progressive pulmonary injury in experimental animals and contribute to our understanding of the pathogenesis of human lung disease. BIBLIOGRAPHIC REFERENCES: Kravis, T.C. and Henson, P.M. Release of platelet-activating factor (PAF) from sensitized rabbit lung. Fed. Proc., 33: 797, In press, 1975.